Luminal epithelium remodeling underlies endometrial regeneration during menstruation and pregnancy

Menstruation and pregnancy impose an immense regenerative burden on the endometrium. These events breach the luminal epithelium lining the uterine cavity, which is proposed to be replenished by cells in adjoining epithelial glands. In contrast to this gland-centric model, we find that luminal and glandular epithelia are maintained by separate progenitor populations during homeostasis, induced menstruation, pregnancy, and postpartum repair in mice. Although our data indicate that gland cells do not contribute substantially to luminal epithelium regeneration under physiological conditions, we find that they can serve as facultative progenitors that resurface the tissue after chemical ablation. During menstruation, the luminal epithelium bypasses the need for gland contributions by undergoing extensive expansion and morphogenesis to re-epithelialize stromal surfaces concurrently with tissue breakdown. Analogous morphogenesis occurs during gestation, revealing luminal epithelial expansion as a unifying mechanism enabling simultaneous stromal disruption and re-epithelialization, which may underlie the endometrium's remarkable regenerative capacity.